Novel type 1 5a-reductase Inhibitors with Antiproliferative Potential on LNCaP cells

Abstract

This study demonstrated the antiproliferative potential of several dehydroepiandrosterone derivatives 2a-b, 3a-f, and 4a-f in LNCaP cells. LNCaP cells were cultured in the presence of the vehicle, dihydrotestosterone, or testosterone plus 2a-b, 3a-f, 4a-f, or finasteride. At 24 h the 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyltetrazolium bromide-test was performed to determine cell proliferation. In addition, the kinetic of SRD5A1 in these cells was studied in the presence or absence of different concentrations of 2a. Testosterone and dihydrotestosterone increased the proliferation of LNCaP compared to the vehicle-treated cells. Furthermore, steroids 2a-b, 3a-f, and 4a-f decreased the number of viable cells compared to testosterone treatment. However, finasteride did not affect viability. LNCaP cells converted radiolabeled testosterone into dihydrotestosterone. This conversion was inhibited by high concentrations of 2a, while at a pM concentration, the conversion increased slightly, suggesting the presence of allosteric sites in SRD5A1. In conclusion, the three series of derivatives of dehydroepiandrosterone significantly decreased the number of viable LNCaP cells, therefore, showing therapeutic potential to treat metastatic prostate cancer.